FDA issues pregnancy warning on troubled ingredient vinpocetine
FDA based its warning on a National Toxicology Program report on vinpocetine in rats and rabbits. The report, which has yet to undergo final peer review, found developmental toxicity for the ingredient in both species, with the clearest evidence in rats. FDA said for women this means there is a possibility that the ingredient could cause miscarriages or harm fetal development.
Vinpocetine, generally thought of as a nootropic ingredient, was at one time thought to be of most interest for older adults who were concerned about forestalling cognitive decline. But with the popularity of ‘biohacking’ concepts, in which consumers of all ages are looking for dietary interventions of many different to boost physical performance and cognitive performance, the agency said there is a risk of significant exposures for women of childbearing age.
“These findings are particularly concerning since products containing vinpocetine are widely available for use by women of childbearing age. That’s why today we’re advising pregnant women and women who could become pregnant not to take vinpocetine. We are also advising firms marketing dietary supplements containing vinpocetine to evaluate their product labeling to ensure that it provides safety warnings against use by pregnant women and women who could become pregnant,” FDA wrote in its warning.
Successful NDIs don’t preclude subsequent troubles
Vinpocetine has had a checkered regulatory history. The ingredient had five positive NDI notifications for the ingredient in the late1990s (Amrion Inc (1997), Leiner Health Products (1998 & 1999), GNC (1999), and Pharmavite (1999). But FDA announced on September 7, 2016 that it was seeking comment on the regulatory status of the ingredient after tentatively concluding that vinpocetine is not a dietary ingredient.
After more than six months of working through the more than 800 comments the agency received on its request, it tentatively ruled that vinpocetine is not a legal dietary ingredient, which is where the matter stood until the warning issued yesterday.
Vinpocetine, a compound positioned for brain health formulations, is derived from vincamine obtained from the lesser periwinkle plant (Vinca minor L.) and there is evidence to support its role as a vasodilator – or increasing blood flow to the brain. It’s being investigated as a drug in many countries but is not permitted as a pharmaceutical in the US, instead being sold as a supplement.
Two factors underpin regulatory stance
FDA’s tentative decision that vinpocetine is not a legal dietary ingredient hinged on two factors:
- FDA said a search of its files reveals that the ingredient was the subject of an Investigation New Drug application in 1981 and that multi-center trials on the substance were conducted in the mid-1980s. Under Federal law a compound can first be marketed as a dietary supplement and then developed into a drug, but not vice versa, so an IND filing pre-empts a supplement application. One view of this provision of the law is to protect the huge investment that pharmaceutical companies must make to bring new drugs to market;
- Vinpocetine is synthetic. Since the release of the first NDI draft guidance in 2011 and re-released in updated form just a few weeks ago, the agency has taken the tack that bioidentical compounds, or so-called ‘synthetic botanicals’ do not qualify as dietary ingredients because synthetic compounds, even if they are identical in all respects to their botanical progenitors, did not themselves arise from plants and therefore don’t meet the definition of a dietary ingredient. “Vinpocetine is not found in V. minor, Voacanga, or any other botanical, but rather is a synthetic derivative of vincamine or tabersonine,” the agency said.
In the warning issued yesterday, the agency did not further clarify vinpocetine’s regulatory status.
Over the top dosages
Dan Fabricant, PhD, president and CEO of the Natural Products Alliance, said the NTP study used dosages that don’t equate well to what a consumer would experience in the marketplace.
“For most products on the shelf, the dose is 10 mg. For the toxicity study, they were feeding the rats 1,000 times of what a human would get,” Fabricant said.
“I think the agency is a bit out over the skis on this,” he said.
Vulnerable populations demand caution
Andrew Shao, PhD, interim chief science officer of the Council for Responsible Nutrition, said it’s prudent to err on the side of caution when considering a vulnerable population like women who are or could get pregnant.
But he the situation with vinpocetine did not include what many of these situations that generate these kinds of consumer warnings do, and that is a clear incidence of harm in the marketplace.
Vinpocetine’s cardinal sin: It doesn’t fit paradigm
Rather, vinpocetine has the one toxicity study (which Shao cautioned has yet to go through final peer review), and it has another quirk: It doesn’t fit the current regulatory paradigm for how FDA looks at synthetic copies of naturally occurring botanical constituents.
“With pregnant women, looking at it from FDA’s standpoint you’d want to take a more conservative approach. But if we really look at the totality of the situation we are a little perplexed at this warning,” Shao said.
“Vinpocetine was successfully notified to the agency on a number of occasions. Those notices preceded the agency’s position that synthetic copies of botanical ingredients cannot be legal dietary ingredients. FDA had a chance to look at these things before and didn’t come back with concerns,” he said.
“We’ll have to monitor how the NTP gets finalized and how that information is subsequently communicated. Maybe FDA is trying to stack the deck a bit for defending its policy decision on synthetic botanicals. As far as we know for now, though, this was purely a safety issue. So one thing might not necessarily have anything to do with the other,” Shao added.
